The invention relates to a new medical use for compounds which act as inhibitors of cyclooxygenase-2 (COX-2).
It is only recently that the enzyme COX has been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is largely responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be largely responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1.
COX-2 inhibitors may be identified by methods well known in the art, for example as described in WO99/12930 (especially pages 25 and 26).
In various animal models, by-products of the COX pathway have been shown to be inhibitory to gastrointestinal motility. Specifically, stimulation in motor activity occurs following administration of non-selective COX inhibitors, such as indomethacin, and inhibition in motor activity follows exogenous administration of some prostaglandins. Additionally, intravenous administration of indomethacin has also been shown to increase lower esophageal sphincter pressure (LESP) in man. The observed changes in motor activity have been attributed to products of the COX-1 pathway, since the trigger for induction of COX-2, the inducible isoform of the COX enzyme, is not readily apparent.